Biology subjects

Varga, Z.

Publications and source records attributed to Varga, Z..

12 recordsLinked to original sources

bioRxiv2026

A preclinical resistance framework discovers the virulence risks of antibiotics in development

Several new antibiotics target multidrug-resistant pathogens, yet resistance is still evaluated mainly by drug-susceptibility, leaving consequences for bacterial pathogenicity poorly understood. Here, we develop a framework integrating resistance evolution, genomic surveillance and host-pathogen phenotyping to classify antibiotics by resistance potential and pathogenic consequences. Applying this framework to Klebsiella pneumoniae identified functionally distinct antibiotic candidates associated with elevated virulence risk. Resistance evolution rapidly increased virulence through clinically-relevant mutations, without direct selection for pathogenicity. Despite distinct genetic routes, resistance converged on cell-envelope rewiring. A single resistance mutation increased epithelial adhesion, intracellular colonization, macrophage immune-evasion, and tissue persistence in murine infection models, transforming K. pneumoniae into a more invasive and cytotoxic pathogen. Risk-profile analysis revealed partial decoupling of resistance and pathogenicity, with some low-resistance antibiotics yielding highly-virulent populations. These findings establish resistance-driven virulence as an underappreciated translational hazard and call for incorporating host-pathogen interactions into resistance surveillance and preclinical antibiotic development.

microbiology↗

bioRxiv2025

Integrated Histology and Molecular Profiling of Postmortem Human Auditory and Vestibular Organs via a Poly(Methyl Methacrylate)-Based Workflow

Hearing and balance disorders are the most prevalent sensory impairments, affecting hundreds of millions worldwide, yet their underlying cellular and molecular pathologies remain poorly understood. This knowledge gap stems from the inaccessibility of the ears sensory organs--embedded within the temporal bone (TB), the hardest bone in the body--which cannot be biopsied in living patients without causing irreversible damage. Conventional histopathology workflows rely on postmortem en bloc extraction of TBs, followed by lengthy decalcification, celloidin embedding, and manual serial sectioning of these large specimens--a process that takes one to two years, is labor- and cost-intensive, and lacks compatibility with most modern protein, DNA, and RNA assays. Here, we present a rapid, reversible polymethyl methacrylate (rPMMA) workflow that enables advanced molecular histopathology studies on formalin-fixed, calcified TBs. Our protocol uses low-temperature (-40 {degrees}C to +4 {degrees}C) resin embedding, precision near-serial sectioning (10-50 {micro}m) via femtosecond laser microtomy or precision diamond wire sawing, and subsequent deacrylation to fully restore tissue accessibility for high-fidelity histomorphology, multiplexed immunofluorescence, whole-genome sequencing, and in situ mRNA detection (RNAscope) assays. Compared to the gold-standard celloidin workflow, our method reduces processing time and costs by approximately 90% while integrating equivalent histomorphology with advanced molecular assays, providing a new benchmark for multidimensional studies in human hearing and balance pathologies.

pathology↗

bioRxiv2025

Genome-wide association study reveals KCNQ3 gene as a risk factor for fear-related behavior in dogs and zebrafish

Freezing behavior, characterised by attentive immobility as a reaction to a perceived threat, is widely studied in the context of fear, anxiety and stress. To uncover the genetic factors underlying this behavior, we conducted a genome-wide association study (GWAS) in kennel-housed beagle dogs. Our analysis identified a single-nucleotide polymorphism (SNP) in intron 5 of the KCNQ3 gene on chromosome 13 associated with freezing behavior in response to unfamiliar environments and people. To validate this finding, we used a zebrafish model, where CRISPR/Cas9-induced kcnq3 deficiencies led to heightened fear and arousal in two behavioral tests. KCNQ3 is implicated in several neurodevelopmental and psychiatric disorders, and our results highlight its evolutionarily conserved role in modulating fear responses. In dogs, an enriched environment can mitigate the adverse effects of KCNQ3 deficiency by reducing threat perception, highlighting the role of gene-environment interactions in shaping behavioral responses. TeaserKCNQ3 influences fear responses across species, with gene-environment interactions shaping freezing behavior in dogs.

animal behavior and cognition↗

bioRxiv2025

A549 tumorigenic and BEAS-2B non-tumorigenic cell line derived small extracellular vesicles show distinct proteomic, N-glycoproteomic and chondroitin/dermatan sulfate profiles

Extracellular vesicles (EVs) are critical mediators of intercellular communication and hold promise as biomarkers and therapeutic targets in cancer, but their molecular alterations remain poorly understood. Protein glycosylation is a frequent post-translational modification; however, most EV studies focus only on proteomics, while mapping glycosylation changes of proteins are still underrepresented. To address this shortcoming, we analyzed the proteomic, N-glycoproteomic, and chondroitin/dermatan sulfate (CS/DS) glycosaminoglycan (GAG) profiles of small EVs (sEVs) derived from A549 lung adenocarcinoma and BEAS-2B non-tumorigenic epithelial cell lines. Principal component analysis and hierarchical clustering revealed that all three profiles are highly dependent on the origin of sEV, highlighting fundamental differences not only at the proteomic but also at the N-glycopeptide and CS/DS levels. Protein expression differences were primarily associated with the upregulation of cell cycle regulation, DNA repair, metabolism, and protein synthesis, while immune-related processes were predominantly downregulated. Proteomics revealed differential expressions of 5 CS proteoglycans, anticipating that their CS profile may also change. N-glycoproteomics highlighted a shift from complex to hybrid N-glycans in cancer sEVs, alongside a significant decrease in fucosylation. Prominent glycoproteins characterized with multiple glycosylation sites included versican, galectin-3-binding protein and laminins. The total amount of CS/DS increased 3.4-fold in cancer sEVs, while the ratio of the two monosulfated disaccharides changed 2-fold, suggesting altered sulfation mechanisms. These findings highlight the potential of N-glycoproteomics and GAG profiling to enhance biomarker discovery and EV-based cancer diagnostics. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/643059v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@c2dfdeorg.highwire.dtl.DTLVardef@1f79452org.highwire.dtl.DTLVardef@12a9dbborg.highwire.dtl.DTLVardef@d992da_HPS_FORMAT_FIGEXP M_FIG C_FIG Proteomic, N-glycoproteomic and chondroitin/dermatan sulfate disaccharide profiles differ between A549 lung adenocarcinoma and BEAS-2B non-tumorigenic epithelial cell derived small extracellular vesicles.

cancer biology↗

bioRxiv2025

Transposon insertion causes ctnnb2 transcript instability that results in the maternal effect zebrafish ichabod (ich) mutation

The maternal-effect mutation ichabod (ich) results in ventralized zebrafish embryos due to impaired induction of the dorsal canonical Wnt-signaling pathway. While previous studies linked the phenotype to reduced ctnnb2 transcript levels, the causative mutation remained unidentified. Using long-read sequencing, we discovered that the ich phenotype stems from the insertion of a non-autonomous CMC-Enhancer/Suppressor-mutator (CMC-EnSpm) transposon in the 3UTR of the gene. Through reporter assays, we demonstrate that while wild type ctnnb2 mRNAs exhibit remarkably high stability throughout the early stages of development, the insertion of the transposon dramatically reduces transcript stability. Genome-wide mapping of the CMC-EnSpm transposons across multiple zebrafish strains also indicated ongoing transposition activity in the zebrafish genome. Our findings not only resolve the molecular basis of the ich mutation but also highlight the continuing mutagenic potential of endogenous transposons and reveal unexpected aspects of maternal transcript regulation during early zebrafish development.

developmental biology↗

bioRxiv2024

Survival cost sharing among altruistic full siblings in Mendelian population

BackgroundWe focus on Haldanes familial selection in monogamous families in a diploid population, where the survival probability of each sibling is determined by altruistic food sharing with its siblings during starvation. An autosomal recessive-dominant or intermediate allele pair uniquely determines the altruistic or selfish behavior, which are coded by homozygotes. We focus on the case when additive cost and benefit functions determine the survival probability of each full sibling. ResultsWe provide conditions for the existence of the altruistic and selfish homozygote. We show that the condition of evolutionary stability of altruism depends on the genotype-phenotype mapping. Furthermore, if the offspring size increases then the condition of evolutionary stability of altruism becomes stricter. Contrary to that, for the evolutionary stability of selfish behavior it is enough if the classical Hamiltons rule does not hold. Moreover, when the classical Hamiltons rule holds and the condition of evolutionarily stability of altruism does not hold, then the selfish and altruistic phenotypes coexist. ConclusionsIn summary, the classical Hamiltons rule is a sufficient condition for the existence of altruism, but it alone does not imply the evolutionary stability of the pure altruistic homozygote population when the altruistic siblings share the cost of altruism.

evolutionary biology↗

bioRxiv2024

Do organisms need an impact factor? Citations of key biological resources including model organisms reveal usage patterns and impact.

Research resources like transgenic animals and antibodies are the workhorses of biomedicine, enabling investigators to relatively easily study specific disease conditions. As key biological resources, transgenic animals and antibodies are often validated, maintained, and distributed from university based stock centers. As these centers heavily rely largely on grant funding, it is critical that they are cited by investigators so that usage can be tracked. However, unlike systems for tracking the impact of papers, the conventions and systems for tracking key resource usage and impact lag behind. Previous studies have shown that about 50% of the resources are not findable, making the studies they are supporting irreproducible, but also makes tracking resources difficult. The RRID project is filling this gap by working with journals and resource providers to improve citation practices and to track the usage of these key resources. Here, we reviewed 10 years of citation practices for five university based stock centers, characterizing each reference into two broad categories: findable (authors could use the RRID, stock number, or full name) and not findable (authors could use a nickname or a common name that is not unique to the resource). The data revealed that when stock centers asked their communities to cite resources by RRID, in addition to helping stock centers more easily track resource usage by increasing the number of RRID papers, authors shifted from citing resources predominantly by nickname ([~]50% of the time) to citing them by one of the findable categories ([~]85%) in a matter of several years. In the case of one stock center, the MMRRC, the improvement in findability is also associated with improvements in the adherence to NIH rigor criteria, as determined by a significant increase in the Rigor and Transparency Index for studies using MMRRC mice. From this data, it was not possible to determine whether outreach to authors or changes to stock center websites drove better citation practices, but findability of research resources and rigor adherence was improved.

bioinformatics↗

bioRxiv2022

Isolation and genome characterization of Lloviu virus from Italian Schreibers bent-winged bats

Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers bent-winged bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its discovery. Studies with recombinant and wild-type LLOV isolates confirmed the susceptibility of human-derived cell lines and primary human macrophages to LLOV infection in vitro. Based on these data, LLOV is now considered as a potential zoonotic virus with unknown pathogenicity to humans and bats. We examined bat samples from Italy for the presence of LLOV in an area outside of the currently known distribution range of the virus. We detected one positive sample from 2020, sequenced the complete coding sequence of the viral genome and established an infectious isolate of the virus. In addition, we performed the first comprehensive evolutionary analysis of the virus, using the Spanish, Hungarian and the Italian sequences. The most important achievement of this article is the establishment of an additional infectious LLOV isolate from a bat sample using the SuBK12-08 cells, demonstrating that this cell line is highly susceptible to LLOV infection. These results further confirms the role of these bats as the host of this virus, possibly throughout their entire geographic range. This is an important result to further understand the role of bats as the natural hosts for zoonotic filoviruses.

microbiology↗

bioRxiv2019

MATRIEX Imaging: Multi-Area Two-photon Real-time In-vivo Explorer

Two-photon laser scanning microscopy, originally developed since 1990s1, has been widely applied for biomedical research in recent decades, particularly popular among neuroscientists for studying neural functions in vivo2. However, it is typically restricted to one imaging area that is orthogonal to the optical axis. Here, we demonstrate a novel multi-axis optical conjugation method that enables two-photon imaging at single-cell resolution simultaneously in multiple areas at different depths, each of which could have a view diameter of ~200 m and could be largely freely targeted within a zone up to 12-mm diameter. For example, we show simultaneous imaging of neuronal activities in the primary visual cortex (V1), the primary motor cortex (M1) and the hippocampal CA1 region of awake mice. This method can be readily implemented on a single conventional two-photon microscope to enable multi-area exploration of neuronal activities in vivo.

neuroscience↗

bioRxiv2017

Juvenile honest food solicitation and parental investment as a life history strategy: a kin demographic selection model

Parent-offspring communication remains an unresolved challenge for biologist. The difficulty of the challenge comes from the fact that it is a multifaceted problem with connections to life-history evolution, parent-offspring conflict, kin selection and signalling. Previous efforts mainly focused on modelling resource allocation at the expense of the dynamic interaction during a reproductive season. Here we present a two-stage model of begging where the first stage models the interaction between nestlings and parents within a nest and the second stage models the life-history trade-offs. We show in an asexual population that honest begging results in decreased variance of collected food between siblings, which leads to mean number of surviving offspring. Thus, honest begging can be seen as a special bet-hedging against informational uncertainty, which not just decreases the variance of fitness but also increases the arithmetic mean.\n\nAuthor SummaryParent-offspring communication is a fascinating problem that captures the attention of scientist and layman alike. Parent-offspring interaction is the first interaction with non-self in the life of most young birds and mammals. The future life success of such young animals crucially depends on how successful they are in interacting and communicating with their parents. This communication has different functions: it is important for the offspring to solicit food from the parent and it is important for the parent to be informed about the state (hunger level) of the offspring. There is an optimization problem on top of this level: the parent has to decide what part of the available resources should be allocated to the offspring and what part should she keep for herself. Here we show in a probabilistic model that the honest phenotype -where offspring beg only if they are hungry-has a greater growth rate than a selfish type - which begs regardless of its hunger level. This result holds in asexual populations; here honesty serves as a reduction uncertainty for the parents. The improved decision making of the parents -in turn-increases the survival of the offspring as well.

evolutionary biology↗

bioRxiv2017

Caring for parents: an evolutionary rationale

The evolutionary roots of human moral behavior are a key precondition to understand human nature. Here we investigate whether a biological version of Fifth Commandment (\"Honor your father and your mother, that your days may be long\"), respected in different variants across cultures, can spread through Darwinian competition. We show by a novel demographic model that a corresponding Fifth Rule (\"During your reproductive period, give away from your resources to your post-fertile parents\") will spread even if the cost of support to post-fertile grandmothers considerably decreases the demographic parameters of fertile parents but radically increases the survival rate of grandchildren. Teaching vital cultural content is likely to have been critical for the value of grandparental service. Selection on such behavior may have produced an innate moral tendency to honor parents even in situations, such as experienced today, when the quantitative conditions would not necessarily favor the maintenance of this trait.

evolutionary biology↗

bioRxiv2017

Systematic analysis of cell phenotypes and cellular social networks in tissues using the multiplexed image cytometry analysis toolbox (miCAT)

Single-cell, spatially resolved omics analysis of tissues is poised to transform biomedical research and clinical practice. We have developed an open-source computational histology topography analysis toolbox (histoCAT) to enable the interactive, quantitative, and comprehensive exploration of phenotypes of individual cells, cell-to-cell interactions, microenvironments, and morphological structures within intact tissues. histoCAT will be useful in all areas of tissue-based research. We highlight the unique abilities of histoCAT by analysis of highly multiplexed mass cytometry images of human breast cancer tissues.\n\nTechnological advances in the multi-parametric analysis of single cells have revealed an unprecedented heterogeneity of cellular phenotypes and functional states that are concealed in population-based studies1-3. Each cellular phenotype is defined by the interplay of its internal state and the environment in which ...

systems biology↗